Biomarker, Functional Status, and Quality-of-Life Trajectories Before Modes of Death in Heart Failure

Importance: Sudden death remains a leading cause of mortality in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF), but whether these events are preceded by clinical deterioration remains unclear. Objective: To characterize clinical trajectories preceding sudden death in patients with HFmrEF or HFpEF and compare them with trajectories before other modes of death and survival. Design, Setting, and Participants: This was a post hoc analysis of the Finerenone Trial to Investigate the Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) randomized clinical trial evaluating trajectories of functional status, patient-reported health status, and natriuretic peptide levels preceding adjudicated modes of death. This was a global, event-driven clinical trial. Patients with symptomatic HF, left ventricular EF of 40% or greater, New York Heart Association class (NYHA) II to IV, and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were enrolled between September 14, 2020, and January 10, 2023. Data analysis was conducted in December 2025. Interventions: Finerenone vs placebo. Main Outcomes and Measures: Longitudinal trajectories of NYHA class, Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), and NT-proBNP levels preceding sudden death were compared with trajectories in survivors and those who died of HF-related, nonsudden cardiovascular, or noncardiovascular causes, using linear mixed-effects models with restricted cubic splines. Results: Included in this analysis were 6001 patients (mean [SD] age, 72.0 [9.6] years; 3269 male [54%]). Over a median (IQR) follow-up of 2.7 (1.9-3.0) years, 215 sudden deaths occurred. In the 6 months before death, sudden death was preceded by a slight worsening in physician-assigned NYHA class (from approximately 2.3 to 2.4), worsening self-reported health status (an approximately 8-point decline in KCCQ-TSS), and a gradual rise in NT-proBNP levels (from approximately 1800 to 2000 pg/mL). In contrast, among patients who survived, NYHA class improved (from approximately 2.3 to 2.1), KCCQ-TSS increased (from approximately 68 to 77), and NT-proBNP levels declined (from approximately 800 to 650 pg/mL) over the 18 months before the end of follow-up. Comparable patterns of deterioration to those preceding sudden death, often more pronounced, were observed before other modes of death. Conclusions and Relevance: Results of this post hoc analysis of the FINEARTS-HF randomized clinical trial reveal that in this contemporary HFmrEF or HFpEF cohort, sudden death was preceded by modest worsening of symptoms, declining quality of life, and rising natriuretic peptide levels, suggesting many of these events may not have been entirely sudden. However, similar deterioration preceding other modes of death suggests limited specificity for sudden death. Trial Registration: ClinicalTrials.gov Identifier: NCT04435626.